Understanding IDH mutant gliomas

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

In the past year, we made progress in both preclinical and clinical settings. Preclinically, we we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient's sample retaining endogenous expression of IDH R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level. Clinically, we have completed the enrollment to the clinical trial 19C0006, which was designed to elucidate the impact of tumor mutational burden on the response to the immune checkpoint inhibitor treatment in IDH-mutant gliomas. We are in the process of analyzing the correlative studies to understand the factors that are associated with the treatment response. The results of the primary and secondary objectives of the study will be submitted to clinicaltrials.gov. Another clinical trial 19C0096, "Studying the Biology of Higher-Grade Transformation in IDH-mutant Gliomas via Longitudinal Observation of Tumor Metabolic Reprogramming Using Non-invasive Metabolic Imaging". The clinical trial protocol was amended to add the HP 13C MRI technology as an important metabolic imaging for the study. We have received the FDA IND approval and successfully launched the study by imaging a study participant with IDH mutant glioma patient.